Hemiasterlin analogs 1 with substituents as reported (WO 9932509) are synthesized by coupling carboxylic acid 2, with intermediate amine 3.

The asymmetric synthesis of N-(tert-butoxycarbonyl)-N,β,β-trimethyl-L-phenylalanine from 3-methyl-3-phenylbutanoic acid using a chiral oxazolidine route is described (WO 9932509). In particular, this route is limited to small scale synthesis because trisyl azide as a reagent is a safety hazard and the azide intermediate produced therefrom makes this route not suitable for scale-up. Still further, purification in several of the steps requires chromatography and additionally, some racemization in the last synthetic step, makes this route less desirable for the scale-up.
Reported also is the preparation of N,N-di(tert-butoxycarbonyl)-(2S)-2-[(benzothiazole-2-sulfonyl)methylamino]-3-methyl-(1-methylindol-3-yl)butyramide (4, Vedejs, E et. al J. Org. Chem, 2001, 66, 7355–7364) using asymmetric Strecker methodology (Chakraborty, T. K. et. al, Tetrahedron Letters, 1991, 32, 7597–7600). However, the described synthetic methodology cannot be used effectively for scaleup in the synthesis of acid 2 because of the use of tributyltin cyanide and the necessary purification of intermediates by column chromatography.

Thus, there is need in the art for a process to prepare carboxylic acid 2 which overcomes azide intermediates and also overcomes the need for purification by column chromatography.
Further, there is a need for a synthesis of carboxylic acid 2, in particular (S), which is used in the preparation of hemiasterlin analogs 1.
In particular, there is a need for a process to prepare (S) acid 2 used to prepare N,β,β-trimethylphenylalanyl-N1-[(1S,2E)-3-carboxy-1-isopropylbut-2-enyl]-N1,3-dimethyl-L-valinamide a tubulin inhibitor useful in the treatment of cancer.